Multidrug resistance of the malaria parasite Plasmodium falciparum is a major contributor to the resurgence of malaria in the world. With the failing of many antimalarial drugs, the use of artemisinin and its derivatives has been endorsed by many malaria-endemic countries. Although these are the only class of antimalarial drugs to which there are no confirmed clinical resistance, the reports of artemisinin treatment failures in many regions of the world are of great concern. To prevent or delay the development of artemisinin resistance, artemisinin-based combination therapy (ACT) has been advocated and applied. Yet, the partner drugs vary geographically, depending on the drug history of the regions. To choose the best partner drug for artemisinins for a specific region, it is essential to have a comprehensive knowledge of drug resistance in the parasite populations. In addition, close surveillance for reduced sensitivity of parasites to artemisinins as the early stage of resistance development and better understanding the resistance mechanism are critical for taking adequate countermeasures to prevent and slow down resistance development. In the subtropical Yunnan province of China, malaria is perennial with -300,000 cases per year. In contrast to the recent introduction of artemisinin for malaria therapy elsewhere, artemisinin monotherapy has been the mainstay of malaria chemotherapy in Yunnan for almost three decades. Malaria treatment is mostly family-based and there is a high degree of non-compliance to the drug regimens, which favors resistance development. Our past surveillance has detected a significant proportion of parasite field isolates with more than three-fold decrease in susceptibility to artemisinins and their derivatives. Based on the unique malaria drug history in Yunnan and the lack of a comprehensive picture of drug resistance in the parasite populations, we propose to (1) systematically evaluate parasite's sensitivity to a wide range of antimalarials;and (2) determine the polymorphisms in known and putative molecular markers of drug targets and evaluate their associations with in vitro drug resistance. Clinical parasite isolates before and after artesunate monotherapy will be assayed for responses to antimalarials and genotyped for polymorphisms in known and putative resistant markers. The integration of accurate drug assays and molecular analysis will provide essential information for elucidating the mechanism of artemisinin resistance, understanding how drug resistance evolves, and helping local policy makers select the most appropriate ACTs. Malaria resurgence is partially due to the emergence and spread of multidrug resistant parasites. Resistance surveillance and elucidation of resistance mechanisms for antimalarial drugs, especially for artemisinin family drugs, are important for malaria control.